It is known that a metabolic route called the 5-lipoxygenase route exists in arachidonate cascade and that arachidonate is converted to 5-hydroperoxyeicosatetraenoic acid (hereinafter may be described as 5-HPETE) by the function of 5-lipoxygenase ("Prostaglandin and Morbid States", edited by Seiitsu Murota, Tokyo Kagaku Dojin, 1984).
It is known that various leukotrienes are biosynthesized with this compound as an intermediate ("Prostaglandin and Morbid States", edited by Seiitsu Murota, Tokyo Kagaku Dojin, 1984), and it is also known that, for example, leukotriene B4 of these leukotrienes has a strong leukocyte migration effect and is a mediator of inflammations and that leukotriene C4 and D4 are mediators of asthma ("Prostaglandin and Morbid States", edited by Seiitsu Murota, Tokyo Kagaku Dojin, 1984).
Hence, searches for medicines having an inhibitory effect to 5-lipoxgenase have been performed broadly, from the viewpoint that if there is a medicine capable of inhibiting 5-lipoxgenase, an incipient enzyme of the biosynthesis system of these leukotrienes, effectively, the prevention and remedy effects of various diseases caused by the excess occurrence of leukotrienes (e.g., allergic diseases, bronchial asthma, dropsical swellings, various inflammatory diseases) may be anticipated.
On the other hand, a metabolic route called the 12-lipoxygenase route exists in arachidonate cascade. 12-lipoxygenase is an enzyme existing mainly in platelets and forms 12-hydroperoxyeicosatetraenoic acid (hereinafter may be described as 12-HPETE) according to a reaction with arachidonate, and the compound becomes 12-hydroxyeicosatetraenoic acid (hereinafter may be described as 12-HETE) according to reduction.
The physiological meaning of metabolic products on the 12-lipoygenase route has not been clear compared with that of the 5-lipoxgenase route; however, various physiological activities of the metabolic products have been made clear recently with 12-HPETE and 12-HETE of the main metabolic products at the center.
These physiological activities can be exemplified as below. Namely, regarding the metabolic product of 12-lipoxgenase, a possibility is pointed out that it may play a part in arteriosclerosis by accelerating functional control such as the aggregation and adhesion of platelets and the migration of vascular smooth muscle cells ("Gendai Iryo", Vol. 21, No. 11, pp. 3109-3113, 1989); a possibility is suggested that 12-HPETE may be an initiator for the occurrence of vasospasm after subarachnoid hemorrhage ("Gendai Iryo", Vol. 21, No. 11, pp. 3127-3130, 1989); in addition, it is shown that 12-HETE accelerates the adhesion and metastasis of some cancerous cells to vascular endothelial cells ("Gendai Iryo", Vol 22, special issue pp. 56-57, 1990)
According to the above facts, it is anticipated that substances inhibiting 12-lipoxgenase can be used effectively as medicine for the prevention and remedies of various circulatory diseases such as arteriosclerosis and vasospasm and the prevention of the metastasis of some cancers.
As a substance having an inhibitory effect to 12-lipoxygenase is known baicalein, a kind of natural flavonoid ("Biochemical and Biophysical Research Communications", Vol. 105, No. 3, pp. 1090-1095 1982).
In addition, a hydroxamic acid derivative (official gazette of Japanese Patent Kokai Publication No. 216961/1989, official gazette of Japanese Patent Kokai Publication No. 75 2/1990, official gazette of Japanese Patent Kokai Publication No, 196767/1990) and a caffeic acid derivative (official gazette of Japanese Patent Kokai Publication No. 275552/1989, official gazette of Japanese Patent Kokai Publication No. 235852/1990) are known.
On the other hand, a stilbene derivative and an .alpha.,.beta.-diarylacrylonitrile derivative are generally synthesized chemically or separated from the natural world and purified; as compounds similar to the compounds of the present invention are known the following 1) to 6):
1) .alpha.-[(3,4-dihydroxyphenyl)methylene]-4-nitrobenzene acetonitrile "Journal of the Society of Dyers and Colourists", Vol. 92, No. 1, p. 14, 1976) PA0 2) .alpha.-[(3,4-dihydroxy-5-nitrophenyl)methylene]-2-pyrimidine acetonitrile ["Journal of Computer-Aided Molecular Design", Vol. 6, No. 3, p. 253, 1992) PA0 3) .alpha.-[(3,4-dihydroxyphenyl)methylene]-3,4-dihydroxybenzene acetonitrile (specification of U.S. Pat. No. 4,015,017) PA0 4) 2-(p-azidophenyl)-3-(3,4-dihydroxyphenyl)acrylonitrile (specification of French Invention Patent No. 1,513,907) PA0 5) .alpha.'-cyano-3',4'-dihydroxy-4-stilbene carboxylic acid (specification of U.S. Pat. No. 2,766,271) PA0 6) .alpha.'-(diphenylmethylene)-3,4-dihydroxy-benzene acetonitrile (specification of West Germany Patent Publication No. 2,501,443)
However, it has not been known at all that these compounds have 12-lipoxgenase inhibitory activities.
Incidentally, 12-lipoxgenase is an enzyme of relationship of 5-lipoxgenase; and a substance inhibiting either of enzymes may inhibit the other. In fact, a substance which reportedly has 5-lipoxgenase inhibitory activities and shows inhibitory activities also to 12-lipoxgenase is known, and most of hydroxamic acid derivatives are examples thereof.
Regarding the selectivity of inhibitory activities, such substances as can inhibit 12-lipoxgenase strongly and selectively are preferable for the prevention and remedies of diseases such as the above-mentioned circulatory diseases and the metastasis of cancer deemed to be caused mainly by 12-lipoxgenase metabolic products, though it depends upon the object of use.